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Thanks to research breakthroughs in the field of biotechnology, one of the most important new types of medication for the treatment of Crohn’s disease is biologic therapy. These medications are created from living cells – hence the name – and they target specific proteins that cause Crohn’s inflammation. Dr. Stephen Hanauer of the University of Chicago explains how biologic therapies are changing treatment of Crohn’s disease.

Announcer: Welcome .featuredtable { FLOAT: right; MARGIN: 8px 0px 8px 8px; WIDTH: 197px }to this HealthTalk Crohn’s Community show. Before we begin, we remind you that the opinions expressed on this show solely the views of our guests. They are not necessarily the views of HealthTalk, our sponsors or any outside organizations. And, as always, please consult your own physician for the medical advice most appropriate for you.

This show is supported through an unrestricted educational grant from Biogen Idec and Elan Pharmaceuticals, Inc. We thank them for their commitment to patient education. Our guest reports that he has received prior funding from Elan Pharmaceuticals.

Now here’s your host, Rick Turner.

Rick Turner: First, the bad news: There’s still no cure for Crohn’s disease. But the good news is there are more treatment options now than ever before, and many others are on the way. Thanks to research breakthroughs in the field of biotechnology, one of the most important new types of medication for Crohn’s disease is biologic therapy. These medications are produced by live cells, hence the name biologics, and they target specific proteins that cause Crohn’s inflammation. Today, we’re going to talk about biologic medications and how they’re used to treat Crohn’s disease with Dr. Steven Hanauer, professor of medicine and clinical pharmacology and chief of the section of gastroenterology and nutrition at the University of Chicago Medical Center. He is one of the world’s leading experts on inflammatory bowel diseases such as Crohn’s.

Dr. Hanauer, welcome to our program.

Dr. Stephen B. Hanauer: Thank you, Rick.

Rick: Let’s start with the basics, biologics 101. What are biologic medications? And what makes them different from other drugs?

Dr. Hanauer: Well, in contrast to conventional drugs that are chemically synthesized, biologic therapies, as you introduced, are usually produced by live cells to target specific proteins or chemicals of inflammation that are overproduced in diseases such as Crohn’s disease, which is an inflammatory disease. And also usually different from conventional therapies that are given by mouth, the biologic therapies usually need to be given either as an injection under the skin or in the muscle, or given intravenously directly into the bloodstream. « end custom« end custom

Rick: So biologic therapies can’t be produced simply by combining a couple of chemicals in a test tube.

Dr. Hanauer: Exactly. We need live cells, either cell cultures or even bacteria to produce these chemicals.

Rick: Describe that process a little bit. Is it like brewing beer?

Dr. Hanauer: In many ways, it is actually a brewing process where the genes to produce antibodies, for instance, are actually introduced into bacteria that then produce the proteins or antibodies that are then harvested, clarified and made pure so that they can be injected into humans.

Rick: As of today, what’s the status of available biologics for Crohn’s, doctor?

Dr. Hanauer: There are many different biologics available for other conditions, and some of the biologics that are also approved for Crohn’s disease are approved for other indications, in particular, rheumatoid arthritis. But the currently approved biologic therapies for Crohn’s disease are basically two as of today’s date (August 23, 2007), and that is infliximab, which is marketed as Remicade, and adalimumab, which is marketed as Humira. Both of these are antibodies that target a chemical of inflammation called tumor necrosis factor, or TNF.

At the present time, there is one other protein or antibody that is targeting TNF that is under review but not yet marketed by the FDA, and that compound is called certolizumab and eventually may be marketed as Cimzia.

And there is one other biologic called natalizumab that is marketed already for multiple sclerosis under the name of Tysabri that is a very different type of antibody. That is under review by the FDA and has been approved by the panel recommending the FDA for approval for Crohn’s disease. And this, instead of targeting the compound tumor necrosis factor, targets a molecule that allows blood cells to land on blood vessels and prevents these blood cells from getting into the tissues. So it’s very different from the anti-TNFs [Medical editor’s note: but is still a biologic and still is to reduce inflammation].

Rick: The two that you mentioned which currently are approved, Remicade and Humira, how are they different if they both target TNF?

Dr. Hanauer: They’re different in that Remicade, or infliximab, is what’s known as a chimeric antibody. It has a portion of a mouse antibody that is attached to a human backbone and that’s called a chimera. And Remicade is administered intravenously to patients. In contrast, Humira is a totally human antibody. Now, remember, it’s not made by humans, but there are no mouse components (genes) in the cells that produce Humira. And instead of being administered intravenously, Humira is administered under the skin or what we call subcutaneously. [Medical editor’s note: Humira has not been shown to be any better than Remicade and the presence of the mouse component is in many respects completely irrelevant.]

Rick: And is that also true – the nontargeted nature – of the other traditional therapies, the aminosalicylates and immunosuppressants as well as surgery?

Dr. Hanauer: Absolutely. All of these can actually affect multiple inflammatory compounds. Some of them like the aminosalicylates, these are the mesalamine compounds or sulfasalazine, are like anti-inflammatory mops. They actually mop up many different chemical mediators in the body, so they really are not specifically targeted. Similarly, immune suppressant medication can affect multiple cell types in the body, so they affect both T cells and B cells, which are different types of inflammatory cells. And they really lack the specificity and the targeted nature of biologics.

Rick: Earlier in the summer, Dr. Hanauer, you published a paper in the Journal of Gastroenterology saying that biologics had substantially altered the treatment of Crohn’s in recent years. Tell us about that. Explain why that is.

Dr. Hanauer: The first introduction of biologic therapy for Crohn’s disease was the drug infliximab or Remicade, introduced in 1998. And the first group of patients who received Remicade was patients who still had active Crohn’s disease even though they were already taking the aminosalicylates and steroid therapies as well as immunosuppressants. So they had active disease despite all of our conventional agents. And we found with a single infusion of Remicade that the Crohn’s symptoms were subdued in the vast majority of the patients.

We subsequently learned that with continued or what we call maintenance therapy (with Remicade) that you could continue to control the inflammation and actually heal the lining of the intestine and maintain that healing on a long-term basis. So this was really a revelation because patients who weren’t responding to any of our therapies were now suddenly having a good control of their inflammation, and the treatment really restored what we call their quality of life. They were able to go back to school, back to work, resume their social interactions, and for the first time in many years they were feeling well again.

Rick: What makes someone a candidate for one of these biologics? For example, if I’ve just been diagnosed with Crohn’s and my symptoms aren’t too bad, am I going to be offered a biologic as part of my treatment?

Dr. Hanauer: You might be, but, for the most part, we are reserving biologics for the more complicated patients. And the reason is that Crohn’s disease and ulcerative colitis really are a spectrum of conditions. And up to half of the patients who are diagnosed with Crohn’s disease have what we would consider a benign course. Their symptoms can be controlled with medications like mesalamine or antibiotics or steroids that are not absorbed into the body, or even with immune modifiers that have very few side effects. So about half of the patients can be well-controlled on a long-term basis without biologics.

If patients don’t respond to those agents, then the biologics such as Remicade and Humira can really be effective. So I like to say that the punishment has to fit the crime. Patients who have mild disease are usually controlled with conventional agents, but those who have more severe disease or disease that is not responding or progressive disease, particularly patients who have complications like fistula (an abnormal connection or passageway between two organs or vessels that normally do not connect), will respond better to the biologic agents than to the conventional treatments.

Rick: You mentioned earlier that because biologics are composed of living cells they have to be either injected or infused. Talk to us about the typical course of treatment if someone is prescribed a biologic.

Dr. Hanauer: Let me clarify. We’re not injecting the human cells with biologics. The cells are actually producing proteins such as antibodies. So we’re not injecting cells into patients with biologics. We’re injecting purified protein. [Medical editor’s note: Biologics are not composed of living cells. They are purified proteins that have been made by living cells. When ready for injection, it is a purified protein and there is nothing “alive” or “living” in the injection.]

So what we have learned is that Crohn’s disease requires long-term treatment. We can subdue the inflammation. But if we stop the therapy, it tends to come back, and this applies to biologic therapy as well. So for the vast majority of patients, we shut down the inflammation. We call that induction therapy. And usually that requires higher doses up front.

Afterwards, usually after the first six or eight weeks, then we maintain the clinical improvement or the remission by administering either lower doses or less frequent intervals. An example would be Remicade is initially infused, then two weeks later, then six weeks later, and then every eight weeks. And those are intravenous infusions. With Humira for Crohn’s disease, we give four injections under the skin initially, two injections after two weeks and then one injection every other week to maintain the improvement or remission in the patient.

Rick: With an infusion, obviously you have to go to a doctor’s office. Is that also true with Humira with the subcutaneous injections?

Dr. Hanauer: No. With the injections now, it’s very easy to administer by you. You don’t need someone else to do it. And this has been done in rheumatoid arthritis for the past many years. So it’s very easy to teach patients how to administer the subcutaneous injections, and indeed there’s actually a self-injecting pen that patients can use.

Rick: Not unlike insulin injections?

Dr. Hanauer: Exactly. It’s very similar. But fortunately, in contrast to insulin that needs to be administered either daily or several times a day, Humira can be given every other week, sometimes every week, to prevent the Crohn’s disease from reactivating.

Rick: Let’s talk about some of the side effects of these treatments. What are some of the risks associated with the biologics, and are there certain people who shouldn’t take them?

Dr. Hanauer: Let’s just talk about some of the conventional agents to begin with because we need to compare the risks in order to understand this. So with conventional agents, such as steroids, they affect every part of the body, and there are a lot of side effects with steroids: weight gain, acne, high blood pressure, elevated blood glucose that can lead to diabetes and osteoporosis, just to name a few. The immune modulators require dose adjustments to prevent suppression of the bone marrow, which can lead to risk of infection.

The biologic therapies because they are very targeted have very few immediate side effects. They are usually very well-tolerated. But tumor necrosis factor is an important chemical of inflammation, so blocking it does make patients susceptible to certain types of infection, particularly infections that require cells to clear them. So infections such as tuberculosis can be reactivated if patients have been exposed in the past. So the biggest risk, which is quite small, however, is a risk of infection, and about 1 percent of patients treated with the anti-TNF are susceptible to a serious infection. Minor infections occur in most patients anyway throughout a year, such as colds or respiratory infections or flus. It does not seem to increase the risk of these minor infections very much, but we need to be aware of that. [Medical editor’s note: All patients need to be screened for tuberculosis prior to starting an anti-TNF agent.]

And the last thing is because these are foreign proteins our bodies can develop antibodies against these foreign proteins. And if that happens, patients can get allergic-like reactions after these injections, and that might be a skin rash, fever or shortness of breath. But we’ve learned that if we give the higher doses first and then maintain the patients that these allergic-type reactions are very uncommon.

Rick: And how high is the added risk of lymphoma?

Dr. Hanauer: Everyone is concerned about these risks, but we really need to put it into perspective. And when we talk about risks, we talk about two types of risks – the actual risk and the relative risk. The actual risk of a lymphoma in patients treated with biologic therapy is somewhere in the range of about one in a hundred to one in 400. Compared to patients who are not treated, that would be the relative risk, it might be three or four times greater. But that still puts the risk at about one in a hundred, so it’s still exceedingly uncommon.

Rick: And it’s also tricky sometimes to stop and then restart biologic therapy, is that correct?

Dr. Hanauer: Exactly. The reason is that these biologic therapies are still foreign proteins, and our bodies can develop antibodies against them. And it’s just like developing an allergy or what allergists do to desensitize patients. So, for instance, an individual who gets a very low dose of penicillin and then waits and then is re-exposed is susceptible to getting an allergic reaction to penicillin. With a low dose of a biologic and then a long period between dosing, patients can develop antibodies. In contrast, the way to get rid of allergies is to desensitize by giving continuous dosing, and the maintenance therapy actually prevents allergies as well.

Rick: A significant fact of biologic therapy is the price tag. We talked earlier about the elaborate processes needed to produce these substances. These drugs as a class can cost 20 times more per patient per day than conventional medications. Explain to us again why that is. Why are they so expensive, and how are patients coping with these costs?

Dr. Hanauer: I want to talk about the costs in two different ways. The reason the biologics are so expensive is the manufacturing process that we discussed, requiring live cells to be “taught” how to produce proteins that are actually foreign to these cells. You have to develop the gene and insert the gene into the foreign cells, whether they’re bacteria or cell cultures, and then harvest the collection and then purify it. It’s a very intense and costly process to manufacture these.

When we talk about the costs, however, we need to consider the costs in two different bases. You’re absolutely correct, for individuals these can be very expensive. But when we talk about the total cost, for instance in our country of treating Crohn’s disease, the major costs, the biggest part of the cost pie, are hospitalizations and surgeries. And what we found is that the biologic therapies actually reduce the number of patients who have to go into the hospital and reduce of number of operations, X-rays, endoscopies and blood tests that are needed. So while they are very expensive for individual patients, the overall cost for the country with biologic therapies is actually reduced because it lowers the need for hospitalizations and surgeries.

Rick: Dr. Hanauer, given the side effect profile and the cost, do you still think these biologic therapies are a significant step forward for Crohn’s disease?

Dr. Hanauer: At the present time, they are a significant step forward in particular for patients who are not responding. Now, we are looking at giving these therapies earlier to patients, before they have complications. And the biggest problem right now is selecting the patients with earlier disease who are going to need a biologic versus the patients who are going to respond to our conventional therapies. Right now, it’s my impression that the need for steroid therapy is going to be the tipping point in these diseases.

Rick: Why is that?

Dr. Hanauer: Once the patient needs to go on cortisone therapy, the prognosis isn’t very good. Eighty percent of the patients will have a relapse unless they are maintained with an immunomodulator or a biologic therapy. And once starting cortisone therapy in Crohn’s disease, up to 30 percent of patients require an operation within the year. So if we can introduce the biologics before steroid therapy – and this is where I think we’re going in the future – we’ll be able to prevent the side effects from steroids and hopefully modify the disease course so that the patients don’t go on to the inevitable need for an operation or have progressive complications such as strictures or fistula in Crohn’s disease.

Rick: So you see the future of biologics as continuing to evolve, continuing to refine its targetedness, if you will?

Dr. Hanauer: Exactly. We need to be able to select the appropriate patients. And we need additional what we call biomarkers such as blood tests to tell us which patients are going to be the bad prognosis and are going to benefit the most from biologics versus the patients who have a good prognosis and aren’t going to need them.

Rick: What advice do you have, doctor, for patients who are listening to this conversation and might be interested in talking to their doctors about biologics?

Dr. Hanauer: I think that if the patients are doing well and not having side effects from their ongoing therapy, they probably are not going to need a biologic therapy. On the other hand, if they’re having continued symptoms or side effects from steroids or other treatments, then they should certainly talk to their doctor about what the biologics might do for them.

Rick: In going into this whole decision-making process, does insurance coverage play a role?

Dr. Hanauer: I hate to say that the treatment should depend on insurance coverage, but that’s one of the practicalities of our current situation right now. Because of the individual cost for biologics, it really is necessary to make certain that this therapy is covered, and most insurance plans cover it. But the biggest issue I find is the co-payment because these therapies can cost between two and five thousand dollars a month. And if we have a co-payment that’s substantial, that can really make a big impact on individuals.

Rick: I understand that even for people who don’t have health insurance the companies who manufacture these biologic therapies do offer what they call patient assistance programs to help out.

Dr. Hanauer: Absolutely. And you really should check with your physician and maybe even contact the pharmaceutical companies directly to find out what kind of patient assistance programs they have.

Rick: We’re just about out of time, Dr. Hanauer. Is there anything more you would like to add as a final thought about biologic therapy in Crohn’s disease?

Dr. Hanauer: As I said in the beginning, biologic therapy really has changed the course of patients with bad Crohn’s disease. We are looking to identify patients for whom earlier therapy, what we would call top-down therapy, is most appropriate. And we’re continuing to do studies to improve not only the risk of biologic therapy but the pharmacoeconomics to allow these types of therapies to be available for patients to change the real long-term course of Crohn’s disease as we’ve seen it’s already starting to do over the past decade.

Rick: Once again, I want to thank Dr. Steven Hanauer for joining us today for our show, Biologics in the Fight Against Severe Crohn’s.

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